CHAPTER 118

Prion Diseases

Prion diseases (transmissible spongiform encephalopathies) are rare degenerative diseases of the brain thought to be caused by a protein that converts to an abnormal form called a prion.

Before prions were identified, diseases such as Creutzfeldt-Jakob disease and other spongiform encephalopathies were thought to be caused by viruses. Prions are much smaller than viruses and differ from viruses, bacteria, and all living cells because they do not contain any genetic material. In prion diseases, a normal protein called cellular prion protein (PrPc) changes shape and becomes an abnormal protein molecule called scrapie prion protein (PrPsc)—prion. (Scrapie refers to a prion disease first observed in sheep.) The newly formed prion then converts other nearby PrPc into prions, and the process continues. When prions reach a certain number, disease results. Prions never convert back into PrPc.

PrPc occurs in all cells of the body, with a high concentration in the brain. Consequently, prion diseases affect the nervous system predominantly or exclusively. When these proteins are converted into prions, they usually cause tiny bubbles to form in brain cells. Gradually, the affected cells die and the brain becomes filled with holes. When samples of brain tissue are viewed through a microscope, they somewhat resemble Swiss cheese or a sponge (hence the term “spongiform”).

Prion disease may occur in families because people can inherit a mutation in the gene for PrPc. The mutation makes PrPc molecules more likely to convert to prions. Many different mutations exist. Each mutation generally causes different prion diseases, which, however, fit into three groups: familial Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease.

Prion diseases may occur spontaneously without any known reason. They are called sporadic and are the most common of all human prion diseases, accounting for 85 to 90% of all cases.

Prion diseases can also be acquired when prions originate from an external source, such as contaminated beef—as occurs in variant Creutzfeldt-Jakob disease (vCJD, sometimes called the human version of “mad cow disease”), implant of infected prion tissues, inoculation of prion-contaminated drugs, or use of prion-contaminated neurosurgical instruments. Other potential sources of prion disease besides cattle are elk and deer, which are affected by a prion disease called chronic wasting disease. However, no case of human prion disease has been reported from chronic wasting disease or sheep scrapie. When prions are acquired, symptoms generally develop years later. Kuru also is an acquired prion disease.

Symptoms common to most prion diseases include memory loss, confusion, loss of coordination, muscle twitches, dementia, and gait difficulty.

There is no cure for prion diseases, which are all fatal, usually within months to a few years. Treatment focuses on comfort measures and symptom relief. A number of strategies can help caregivers of people with a prion disease cope with the dementia caused by the disease (see page 691). If possible, people who have a prion disease should establish advance directives (see page 69) about what kind of medical care they want at the end of life. Family members of people who develop the hereditary form of the disease may benefit from genetic counseling.

Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (subacute spongiform encephalopathy) is a prion disease characterized by progressive deterioration of mental function, leading to dementia, muscle twitching (myoclonus), and staggering when walking. A variant form is acquired by eating contaminated beef.

The disease usually occurs spontaneously but may result from eating contaminated beef or from inheriting an abnormal gene.

At first, most people are confused and have memory problems, followed by muscle twitching and loss of coordination.

Most people die with 6 months, although some live for 2 years or more.

The diagnosis can usually be confirmed by electrocephalography, analysis of cerebrospinal fluid, and magnetic resonance imaging.

There is no cure, but drugs can relieve some of the symptoms.

Sporadic Creutzfeldt-Jakob disease, the most common form, affects 1 in a million people each year throughout the world. It affects adults, mainly in their late 50s and 60s. For this form, no cause is known.

Familial CJD results from a mutation in the gene of PrPc, which results in conversion of the normal PrPc molecule to a disease-causing prion. Familial CJD is often inherited and usually starts at an earlier age and lasts longer.

The acquired form includes variant Creutzfeldt-Jakob disease, which is thought to be acquired from the consumption of contaminated beef or beef products. The variant form usually begins around age 30, in contrast to sporadic CJD, which usually begins around age 65. To date, the variant form has been acquired only in Europe, mainly in the United Kingdom, with the exception of two cases acquired in Saudi Arabia. Spread of the disease has been controlled by massive slaughter of cattle in the United Kingdom. Widespread surveillance for the disease in cattle has resulted in a progressively lower number of new cases in the United Kingdom.

External sources for the prion include transplantation of contaminated corneas or possibly other tissues from affected donors and brain surgery using instruments previously used to operate on a person who had CJD. Routine cleansing and sterilization procedures do not destroy prions. However, bleach is effective. Acquiring the disease this way is extremely unlikely.

Another external source is hormones derived from human pituitary glands used for treatment. For example, the disease developed in some children who were treated with growth hormone derived from human pituitary glands. These hormones are now genetically engineered rather than prepared from cadavers, so there is no longer a risk of CJD.

Of Sheep and Cows

Prion diseases occur in sheep, goats, cattle, and other animals, such as minks, elk, deer, and goats. Like people with Creutzfeldt-Jakob disease, affected animals gradually become uncoordinated, then develop dementia. Scrapie, the disease in sheep, is so named because the sheep tend to scrape themselves against fence posts or other objects and tear their wool off. Mad cow disease is so named because the cattle become noticeably agitated. The disease can be transmitted from sheep to cattle by feeding cattle scrapie-infected sheep parts.

Eating contaminated beef or beef products is thought to be the cause of a new form of Creutzfeldt-Jakob disease in people. First described in 1996, this form is called variant Creutzfeldt-Jakob disease (sometimes also called the human version of “mad cow disease”). The new form differs in many ways from the usual form: It causes different changes in brain tissue (seen under a microscope), and the first symptoms tend to be psychiatric symptoms, rather than the memory loss that occurs in people who have the usual form of Creutzfeldt-Jakob disease. By early 2007, variant Creutzfeldt-Jakob disease had been diagnosed in a total of 201 people:

165 in the United Kingdom

21 in France

4 in Ireland

3 in the United States (2 acquired in the United Kingdom, 1 in Saudi Arabia)

2 in Holland

1 in Italy

1 in Japan (acquired in the United Kingdom)

1 in Canada (acquired in the United Kingdom)

1 in Spain

1 in Portugal

1 in Saudi Arabia

Three cases of CJD have been transmitted through blood transfusion. However, in all cases, the disease was acquired from donors affected by the variant form. The type of CJD acquired by medical intervention is called iatrogenic.

CJD has never been reported to be transmitted through casual or even intimate contact with people who have the disease.

Symptoms

The most common early symptoms—memory loss and confusion—may resemble those of other dementias, such as Alzheimer’s disease. In some people, loss of muscle coordination occurs first. In about 10 to 20% of people, symptoms appear abruptly, starting with dizziness and double vision. In people with the variant form, the first symptoms tend to be psychiatric symptoms (such as anxiety or depression), rather than memory loss. Later symptoms are similar in both forms.

Whether symptoms develop gradually or abruptly, mental decline progresses, often producing such symptoms as neglect of personal hygiene, apathy, and irritability. Some people tire easily and become sleepy. Others cannot fall asleep.

Muscles usually begin to twitch involuntarily and quickly during the first 6 months after symptoms begin. Trembling and clumsiness may also develop, and muscle coordination is lost. Walking becomes unsteady, resulting in staggering (similar to the walk of a person who is drunk). Movements may be slow. Impairment of muscle control may result in unusual postures, such as twisting of the trunk or limbs forward and sideways. Muscles may jerk when stretched. The person may startle easily, and the resulting responses, such as jumping when a loud noise is heard, are exaggerated. Startling may trigger muscle twitching. The muscles that control breathing and coughing are usually impaired, increasing the risk of pneumonia. Vision may become blurry or dim.

The symptoms worsen, usually much more rapidly than in Alzheimer’s disease, resulting in severe dementia. Most people with CJD die within 6 months after symptoms appear. About 10 to 20% of people survive for 2 years or more. People with the variant form usually survive for 1 1/2 years. Often, the cause of death is pneumonia.

In people who have acquired the prion from an external source, no symptoms appear for months or years. In the variant form, the time interval between eating contaminated beef and onset of the disease is estimated to be 6 to 12 years.

Diagnosis and Treatment

Doctors consider CJD when mental function is deteriorating quickly, muscle twitching is present, walking is unsteady and staggering, and other dementias have been ruled out by routine testing. The variant form may be considered in people who have typical symptoms and who have eaten processed beef in the United Kingdom or in other countries at risk for mad cow disease.

Diagnosis is mainly by electroencephalography (EEG), analysis of cerebrospinal fluid, and magnetic resonance imaging (MRI). EEG is done to check for specific abnormalities in the electrical activity of the brain, which occur in 70% of people with the disease. A spinal tap is done to obtain a sample of cerebrospinal fluid, which is tested for an unusual protein called 14-3-3. This protein occurs in about 90% of people with typical CJD disease. The EEG abnormalities plus the presence of the 14-3-3 protein in cerebrospinal fluid strongly support the diagnosis of CJD. The absence of the 14-3-3 protein or the characteristic abnormalities on EEG does not rule out CJD. The definitive diagnosis is based on detecting prions in brain tissue by examination of a tissue sample under a microscope or by biochemical analysis at autopsy examination. Diagnostic brain biopsy is occasionally done, generally to rule out a treatable condition, such as inflammation of the brain or encephalitis.

Currently, CJD cannot be cured, and its progress cannot be slowed. The disease is fatal, usually within months or a few years. However, certain drugs may be given to relieve symptoms. For example, the anticonvulsant valproate and the antianxiety drug clonazepam may reduce muscle jerking.

General support and care for the person and family members are important. Day care centers and respite and long-term care may be useful. Speech and occupational therapists can help with specific problems. The CJD Foundation provides support and information

Fatal Familial Insomnia

Fatal familial insomnia is a rare prion disease that interferes with sleep and leads to deterioration of mental and motor functions. Death occurs within a few months to a few years.

Fatal insomnia includes an inherited or familial form, called fatal familial insomnia, due to a specific mutation in the PrPc gene. The disease can also occur spontaneously, without a genetic mutation. This form is called sporadic fatal insomnia. Fatal familial insomnia and sporadic fatal insomnia differ from other prion diseases because they affect predominantly one area of the brain, the thalamus, which influences sleep.

The disease usually begins between the ages of 40 and 60 but may begin in a person’s late 30s. At first, people may have minor difficulties falling asleep and occasional muscle twitching, spasms, and stiffness. Eventually, they cannot sleep. Occasionally, the sleep signs are difficult to detect. Other changes include a rapid heart rate and dementia. Death usually occurs about 7 to 36 months after symptoms begin.

The diagnosis is suggested by typical symptoms and a family history of the disease and can be confirmed by genetic testing. No treatment is available.

Gerstmann-Sträussler-Scheinker Disease

Gerstmann-Sträussler-Scheinker disease is a prion disease that causes muscle incoordination followed by slow deterioration of mental function. The disease is fatal, usually in about 5 years.

Like Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease may occur anywhere in the world. However, it is much less common than Creutzfeldt-Jakob disease, begins earlier in life (affecting people in their 40s rather than in their late 50s and 60s), and progresses more slowly (with an average life expectancy of 5 years rather than 6 months). This disease runs in families.

Usually, the first symptoms are clumsiness and unsteadiness when walking. Muscle twitching is much less common than in Creutzfeldt-Jakob disease. Speaking becomes difficult, and dementia develops. Nystagmus (rapid movement of the eyes in one direction, followed by a slower drift back to the original position), blindness, and deafness may develop. Muscle coordination is lost. The muscles may tremble and become stiff. Usually, the muscles that control breathing and coughing are impaired, resulting in a high risk of pneumonia, which is the common cause of death.

The diagnosis is suggested by typical symptoms and a family history of the disease and can be confirmed by genetic testing. No treatment is available.

Kuru

Kuru is a prion disease that causes rapid deterioration of mental function and loss of muscle coordination. This disease used to occur in the Fore natives of the New Guinea highlands and is related to ritual endocannibalism.

Until the early 1960s, kuru was fairly common in New Guinea. Prions were probably acquired during a cannibalistic ritual accompanying the care of the dead and involving eating tissues of a dead relative as a sign of respect. Kuru probably started from the consumption of prion-contaminated tissues from a person affected by Creutzfeldt-Jakob disease. Kuru was more common among women and children because they were given the brain to eat. Many of these rituals have been abandoned, and kuru has been virtually eliminated.

Symptoms include loss of muscle coordination and difficulty walking. The limbs become stiff, and muscles twitch. Abnormal involuntary movements, such as repetitive, slow writhing or rapid jerking of the limbs and body, may develop (kuru means shivering). Emotions may switch suddenly from sadness to happiness with sudden outbursts of laughter. People with kuru become demented and eventually placid, unable to speak, and unresponsive to their surroundings.

Most people die about 3 to 24 months after symptoms appear, usually as a result of pneumonia or infection due to bedsores (pressure sores).